Glycopyrrolate salts

ABSTRACT

Salts of glycopyrrolate, including solid forms and formulations such as topicals thereof, are disclosed. Methods of making glycopyrrolate salts, including formulations such as topicals thereof, and methods of treating hyperhidrosis with salts of glycopyrrolate, and formulations such as topicals thereof, are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 14/473,537 filed Aug. 29, 2014 (now U.S. Pat. No.9,006,462), which is a continuation of International Patent ApplicationNo. PCT/US2014/019552 filed Feb. 28, 2014, which claims priority to U.S.Provisional Patent Application No. 61/770,920 filed Feb. 28, 2013; U.S.Provisional Patent Application No. 61/770,925 filed Feb. 28, 2013; U.S.patent application Ser. No. 14/024,480 filed Sep. 11, 2013; and U.S.patent application Ser. No. 14/024,484 filed Sep. 11, 2013 (now U.S.Pat. No. 8,859,610). U.S. patent application Ser. Nos. 14/024,480 and14/024,484 are each a continuation application of U.S. patentapplication Ser. No. 13/781,390, filed Feb. 28, 2013 (now U.S. Pat. No.8,558,008). The entireties of each of these applications are herebyincorporated by reference.

BACKGROUND OF THE INVENTION

Glycopyrrolate is a quaternary ammonium cation of the muscarinicanticholinergic group. Glycopyrrolate, typically as a bromide salt, hasbeen used in the treatment of a variety of conditions including diarrhea(U.S. Pat. Nos. 6,214,792 and 5,919,760), urinary incontinence (U.S.Pat. Nos. 6,204,285 and 6,063,808), and anxiety (U.S. Pat. No.5,525,347). Additionally, U.S. Pat. No. 5,976,499 discloses a method fordiagnosing cystic fibrosis in a patient by, in part, stimulating sweatproduction through the injection of a glycopyrrolate solution into apatient. Glycopyrrolate has also been used for the treatment ofhyperhidrosis in US 20100276329.

Hyperhidrosis affects 8.8 million individuals in the United Statesalone, of whom 50.8% are estimated to have axillary hyperhidrosis and25-34% have palmar or plantar hyperhidrosis. Hyperhidrosis is oftentreated with aluminum salts. Applying aluminum salts, such as aluminumchloride, causes frequent skin irritation and is of only limitedeffectiveness. Topically applied glycopyrrolate bromide has been shownto cause less skin irritation and have increased effectiveness overaluminum chloride.

Glycopyrrolate has well-known pharmacology (anticholinergic) and acts asa muscarinic receptor antagonist. As with other anticholinergic agents,glycopyrrolate inhibits the action of acetylcholine on structuresinnervated by postganglionic cholinergic nerves, such as sweat glands.Under physiologic conditions, salts of glycopyrrolate are dissociated;therefore, the pharmacological activity of glycopyrrolate is mediated bythe active cation moiety, also referred to as glycopyrronium.

Glycopyrrolate has previously been made available as a bromide salt oran acetate salt. The bromide salt of glycopyrrolate is sold as Rubinol®.The term “glycopyrrolate” as used in the label for Rubinol® refers tothe bromide salt which is more formally referred to as glycopyrroniumbromide.

A drawback of using bromide salts of pharmaceutical compounds is thepotential for inducing bromism which can result from too high an intakeof bromide. Symptoms of bromism may include neurological abnormalitiessuch as vision impairment and upper motor neuron disorders anddermatologic conditions such as papular and macular rashes. Symptomsmore often develop due to chronic use rather than acute toxicity.

SUMMARY OF THE INVENTION

In one aspect of the invention, a salt of glycopyrrolate is providedwherein the anion is selected from benzoate, edisylate, oxalate,hydrogen sulfate, and tosylate.

In a further aspect of the invention, glycopyrrolate tosylate, includingpolymorphs, co-crystals, hydrates and solvates thereof, is provided.

In a further aspect of the invention, solid glycopyrrolate tosylate isprovided, including polymorphs, solvates, hydrates and co-crystalsthereof and amorphous glycopyrrolate tosylate.

In another aspect of the invention, glycopyrrolate tosylate monohydrateis provided.

In a further aspect of the invention, crystalline glycopyrrolatetosylate, including polymorphs, co-crystals, hydrates and solvatesthereof, is provided.

In a yet another aspect of the invention, crystalline glycopyrrolatetosylate monohydrate and polymorphs thereof are provided.

In another aspect of the invention, Form C glycopyrrolate tosylate isprovided.

In a further aspect of the invention, dehydrated crystallineglycopyrrolate tosylate monohydrate, hereinafter referred to asdehydrated Form D, is provided.

In further aspects of the invention, processes for making Forms C and Dof glycopyrrolate tosylate are provided, as are Form C and Form Dglycopyrrolate tosylate made by those processes.

In an additional aspect of the invention, processes for making threoglycopyrrolate tosylate are provided.

In another aspect of the invention, glycopyrrolate tosylate is provided.

In a further aspect of the invention threo glycopyrrolate tosylate isprovided.

In another aspect of the invention, methods of treating hyperhidrosisusing Forms C or D of glycopyrrolate tosylate are provided.

In another aspect of the invention, amorphous glycopyrrolate tosylate isprovided.

In an additional aspect of the invention, solid dispersions comprisingglycopyrrolate tosylate are provided.

In a further aspect of the invention, a topical comprisingglycopyrrolate tosylate is provided.

In yet another aspect of the invention, processes for preparing anabsorbent pad containing an aqueous solution of glycopyrrolate tosylateabsorbed onto the pad is provided.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the ORTEP drawing of Form D glycopyrrolate tosylatemonohydrate.

FIG. 2 is an x-ray powder diffraction pattern of Form D glycopyrrolatetosylate monohydrate.

FIG. 3 is an infrared (“IR”) spectrum of Form D glycopyrrolate tosylatemonohydrate.

FIG. 4 is the x-ray powder diffraction pattern of Form C glycopyrrolatetosylate.

FIG. 5 is the IR spectrum of Form C glycopyrrolate tosylate.

FIG. 6 is the indexing solution for Form C glycopyrrolate tosylate withPawley refinement.

FIG. 7 includes a DSC thermogram and TGA for Form C glycopyrrolatetosylate.

FIG. 8 is the x-ray powder diffraction for dehydrated Form Dglycopyrrolate tosylate.

FIG. 9 is an overlay of Form D and dehydrated Form D glycopyrrolatetosylate.

FIG. 10 is the indexing solution for dehydrated Form D glycopyrrolatetosylate with Pawley refinement.

FIG. 11 is the indexing solution for Form D glycopyrrolate tosylatemonohydrate with Pawley refinement.

FIG. 12 is the x-ray powder diffraction for crystalline glycopyrrolatebenzoate.

FIG. 13 is the DSC thermogram for crystalline glycopyrrolate benzoate.

FIG. 14 is the x-ray powder diffraction for crystallinedi-glycopyrrolate edisylate.

FIG. 15 is DSC thermogram for crystalline di-glycopyrrolate edisylate.

FIG. 16 is the x-ray powder diffraction for crystalline glycopyrrolateoxalate.

FIG. 17 is the x-ray powder diffraction for crystalline glycopyrrolatehydrogen sulfate.

FIG. 18 is the DSC thermogram for crystalline glycopyrrolate hydrogensulfate.

FIG. 19 is an x-ray amorphous diffraction pattern of glycopyrrolatetosylate.

FIG. 20 is a DSC/TGA overlay of an x-ray amorphous glycopyrrolatetosylate.

FIG. 21 is the x-ray powder diffraction pattern for glycopyrrolatebromide.

FIG. 22 is the x-ray powder diffraction pattern for glycopyrrolateacetate.

FIG. 23 is the modulated DSC thermogram of an x-ray amorphousglycopyrrolate tosylate.

FIG. 24 is an overlay of a portion of the infrared spectrum of a soliddispersion of HPMCAS:glycopyrrolate tosylate (1:1) and its respectivecomponents.

FIG. 25 is the modulated DSC thermogram of a solid dispersion ofHPMCAS:glycopyrrolate tosylate (1:1).

FIG. 26 is the modulated DSC thermogram of a solid dispersion ofsucrose:glycopyrrolate tosylate (9:1).

FIG. 27 a is an overlay of a portion of the infrared spectrum of a soliddispersion of Kollicoat® IR:glycopyrrolate tosylate (1:1) and itsrespective components.

FIG. 27 b is an overlay of a portion of the infrared spectrum of a soliddispersion of Kollicoat® IR:glycopyrrolate tosylate (1:1) and itsrespective components.

FIG. 28 is the modulated DSC thermogram of a solid dispersion ofKollicoat® IR:glycopyrrolate tosylate (1:1).

FIG. 29 is the modulated DSC thermogram of a solid dispersion ofKollicoat® IR:glycopyrrolate tosylate (9:1).

FIG. 30 a is an overlay of a portion of the infrared spectrum of a soliddispersion of Soluplus®:glycopyrrolate tosylate (1:1) and its respectivecomponents.

FIG. 30 b is an overlay of a portion of the infrared spectrum of a soliddispersion of Soluplus®:glycopyrrolate tosylate (1:1) and its respectivecomponents.

FIG. 30 c is an overlay of a portion of the infrared spectrum of a soliddispersion of Soluplus®:glycopyrrolate tosylate (1:1) and its respectivecomponents.

FIG. 31 is the modulated DSC thermogram of a solid dispersion ofSoluplus®:glycopyrrolate tosylate (1:1).

FIG. 32 a is an overlay of a portion of the infrared spectrum of a soliddispersion of PVP K29/32:glycopyrrolate tosylate (1:1) and itsrespective components.

FIG. 32 b is an overlay of a portion of the infrared spectrum of a soliddispersion of PVP K29/32:glycopyrrolate tosylate (1:1) and itsrespective components.

FIG. 32 c is an overlay of a portion of the infrared spectrum of a soliddispersion of PVP K29/32:glycopyrrolate tosylate (1:1) and itsrespective components.

FIG. 32 d is an overlay of a portion of the infrared spectrum of a soliddispersion of PVP K90:glycopyrrolate tosylate (1:1) and its respectivecomponents

FIG. 33 is the modulated DSC thermogram of a solid dispersion of PVPK29/32:glycopyrrolate tosylate (1:1).

FIG. 34 is the modulated DSC thermogram of a solid dispersion of PVPK29/32:glycopyrrolate tosylate (8:1).

FIG. 35 is the modulated DSC thermogram of a solid dispersion of PVPK90:glycopyrrolate tosylate (1:1).

FIG. 36 a is an overlay of a portion of the infrared spectrum of a soliddispersion of Kollidon® VA 64:glycopyrrolate tosylate (1:1) and itsrespective components.

FIG. 36 b is an overlay of a portion of the infrared spectrum of a soliddispersion of Kollidon® VA 64:glycopyrrolate tosylate (1:1) and itsrespective components.

FIG. 36 c is an overlay of a portion of the infrared spectrum of a soliddispersion of Kollidon® VA 64:glycopyrrolate tosylate (1:1) and itsrespective components.

FIG. 37 is the modulated DSC thermogram of a solid dispersion ofKollidon® VA 64:glycopyrrolate tosylate (1:1).

DETAILED DESCRIPTION OF THE INVENTION

The term “solid form” is often used to refer to a class or type ofsolid-state material. One kind of solid form is a “polymorph” whichrefers to two or more compounds having the same chemical formula butdiffering in solid-state structure. Salts may be polymorphic. Whenpolymorphs are elements, they are termed allotropes. Carbon possessesthe well-known allotropes of graphite, diamond, andbuckminsterfullerene. Polymorphs of molecular compounds, such as activepharmaceutical ingredients (“APIs”), are often prepared and studied inorder to identify compounds meeting scientific or commercial needsincluding, but not limited to, improved solubility, dissolution rate,hygroscopicity, and stability.

Other solid forms include solvates and hydrates of compounds includingsalts. A solvate is a compound wherein a solvent molecule is present inthe crystal structure together with another compound, such as an API.When the solvent is water, the solvent is termed a hydrate. Solvates andhydrates may be stoichiometric or non-stoichiometric. A monohydrate isthe term used when there is one water molecule, stoichiometrically, withrespect to, for example, an API, in the unit cell.

In order to identify the presence of a particular solid form, one ofordinary skill typically uses a suitable analytical technique to collectdata on the form for analysis. For example, chemical identity of solidforms can often be determined with solution-state techniques such as¹³C-NMR or ¹H-NMR spectroscopy and such techniques may also be valuablein determining the stoichiometry and presence of “guests” such as wateror solvent in a hydrate or solvate, respectively. These spectroscopictechniques may also be used to distinguish, for example, solid formswithout water or solvent in the unit cell (often referred to as“anhydrates”), from hydrates or solvates.

Solution-state analytical techniques do not provide information aboutthe solid state as a substance and thus, for example, solid-statetechniques may be used to distinguish among solid forms such asanhydrates. Examples of solid-state techniques which may be used toanalyze and characterize solid forms, including anhydrates and hydrates,include single crystal x-ray diffraction, x-ray powder diffraction(“XRPD”), solid-state ¹³C-NMR, Infrared (“IR”) spectroscopy, Ramanspectroscopy, and thermal techniques such as Differential Scanningcalorimetry (DSC), melting point, and hot stage microscopy.

Polymorphs are a subset of crystalline forms that share the samechemical structure but differ in how the molecules are packed in asolid. When attempting to distinguish polymorphs based on analyticaldata, one looks for data which characterize the form. For example, whenthere are two polymorphs of a compound (e.g., Form I and Form II), onecan use x-ray powder diffraction peaks to characterize the forms whenone finds a peak in a Form I pattern at angles where no such peak ispresent in the Form II pattern. In such a case, that single peak forForm I distinguishes it from Form II and may further act to characterizeForm I. When more forms are present, then the same analysis is also donefor the other polymorphs. Thus, to characterize Form I against the otherpolymorphs, one would look for peaks in Form I at angles where suchpeaks are not present in the x-ray powder diffraction patterns of theother polymorphs. The collection of peaks, or indeed a single peak,which distinguishes Form I from the other known polymorphs is acollection of peaks which may be used to characterize Form I. If, forexample, two peaks characterize a polymorph then those two peaks can beused to identify the presence of that polymorph and hence characterizethe polymorph. Those of ordinary skill in the art will recognize thatthere are often multiple ways, including multiple ways using the sameanalytical technique, to characterize polymorphic polymorphs. Forexample, one may find that three x-ray powder diffraction peakscharacterize a polymorph. Additional peaks could also be used, but arenot necessary, to characterize the polymorph up to and including anentire diffraction pattern. Although all the peaks within an entirediffractogram may be used to characterize a crystalline form, one mayinstead, and typically does as disclosed herein, use a subset of thatdata to characterize such a crystalline form depending on thecircumstances.

When analyzing data to distinguish an anhydrate from a hydrate, forexample, one can rely on the fact that the two solid forms havedifferent chemical structures—one having water in the unit cell and theother not. Thus, this feature alone may be used to distinguish the formsof the compound and it may not be necessary to identify peaks in theanhydrate, for example, which are not present in the hydrate or viceversa.

X-ray powder diffraction patterns are some of the most commonly usedsolid-state analytical techniques used to characterize solid forms. Anx-ray powder diffraction pattern is an x-y graph with ° 2θ (diffractionangle) on the x-axis and intensity on the y-axis. The peaks within thisplot may be used to characterize a crystalline solid form. The data isoften represented by the position of the peaks on the x-axis rather thanthe intensity of peaks on the y-axis because peak intensity can beparticularly sensitive to sample orientation (see PharmaceuticalAnalysis, Lee & Web, pp. 255-257 (2003)). Thus, intensity is nottypically used by those skilled in the art to characterize solid forms.

As with any data measurement, there is variability in x-ray powderdiffraction data. In addition to the variability in peak intensity,there is also variability in the position of peaks on the x-axis. Thisvariability can, however, typically be accounted for when reporting thepositions of peaks for purposes of characterization. Such variability inthe position of peaks along the x-axis derives from several sources. Onecomes from sample preparation. Samples of the same crystalline material,prepared under different conditions may yield slightly differentdiffractograms. Factors such as particle size, moisture content, solventcontent, and orientation may all affect how a sample diffracts x-rays.Another source of variability comes from instrument parameters.Different x-ray instruments operate using different parameters and thesemay lead to slightly different diffraction patterns from the samecrystalline solid form. Likewise, different software packages processx-ray data differently and this also leads to variability. These andother sources of variability are known to those of ordinary skill in thepharmaceutical arts.

Due to such sources of variability, it is common to recite x-raydiffraction peaks using the word “about” prior to the peak value in ° 2θwhich presents the data to within 0.1 or 0.2° 2θ of the stated peakvalue depending on the circumstances. The x-ray powder diffraction datacorresponding to the solid forms of glycopyrrolate includingglycopyrrolate tosylate of the disclosure were collected on instrumentswhich were routinely calibrated and operated by skilled scientists.Accordingly, the variability associated with these data would beexpected to be closer to ±0.1° 2θ than to ±0.2° 2θ and indeed likelyless than 0.1 with the instruments used herein. However, to take intoaccount that instruments used elsewhere by those of ordinary skill inthe art may not be so maintained, for example, all x-ray powderdiffraction peaks cited herein have been reported with a variability onthe order of ±0.2° 2θ and are intended to be reported with such avariability whenever disclosed herein and are reported in thespecification to one significant figure after the decimal even thoughanalytical output may suggest higher precision on its face.

Single-crystal x-ray diffraction provides three-dimensional structuralinformation about the positions of atoms and bonds in a crystal. It isnot always possible or feasible, however, to obtain such a structurefrom a crystal, due to, for example, insufficient crystal size ordifficulty in preparing crystals of sufficient quality forsingle-crystal x-ray diffraction.

X-ray powder diffraction data may also be used, in some circumstances,to determine the crystallographic unit cell of the crystallinestructure. The method by which this is done is called “indexing.”Indexing is the process of determining the size and shape of thecrystallographic unit cell consistent with the peak positions in asuitable x-ray powder diffraction pattern. Indexing provides solutionsfor the three unit cell lengths (a, b, c), three unit cell angles (α, β,γ), and three Miller index labels (h, k, l) for each peak. The lengthsare typically reported in Angstrom units and the angles in degree units.The Miller index labels are unitless integers. Successful indexingindicates that the sample is composed of one crystalline phase and istherefore not a mixture of crystalline phases.

IR spectroscopy is another technique that may be used to characterizesolid forms together with or separately from x-ray powder diffraction.In an IR spectrum, absorbed light is plotted on the x-axis of a graph inthe units of “wavenumber” (cm⁻¹), with intensity on the y-axis.Variation in the position of IR peaks also exists and may be due tosample conditions as well as data collection and processing. The typicalvariability in IR spectra reported herein is on the order of plus orminus 2.0 cm⁻¹. Thus, the use of the word “about” when referencing IRpeaks is meant to include this variability and all IR peaks disclosedherein are intended to be reported with such variability.

Thermal methods are another typical technique to characterize solidforms. Different polymorphs of the same compound often melt at differenttemperatures. Thus, the melting point of a polymorph, as measured bymethods such as capillary melting point, DSC, and hot stage microscopy,alone or in combination with techniques such as x-ray powderdiffraction, IR spectroscopy, or both, may be used to characterizepolymorphs or other solid forms.

As with any analytical technique, melting point determinations are alsosubject to variability. Common sources of variability, in addition toinstrumental variability, are due to colligative properties such as thepresence of other solid forms or other impurities within a sample whosemelting point is being measured.

As used herein, the term “glycopyrrolate” refers to the glycopyrroniumcation of the same salt. In other words, as used herein, glycopyrrolateand glycopyrronium are used interchangeably. For example, glycopyrrolatetosylate and glycopyrronium tosylate refer to the same salt.

The present invention provides the tosylate salt of glycopyrrolate or asolvate thereof, including the solution and various solid forms thereof,the process of preparing glycopyrrolate tosylate, and the therapeuticuse of glycopyrrolate tosylate.

By “glycopyrrolate tosylate,” it is meant a tosylate salt ofglycopyrrolate or a tosylate salt of glycopyrronium having the chemicalname of3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-pyrrolidiniumtosylate, also known as“3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate,” and a structure as shown below:

Furthermore, the term “glycopyrrolate tosylate,” as used herein, unlessotherwise specified explicitly or implicitly, such as a glycopyrrolatetosylate resulting from a glycopyrrolate starting material with specificdiastereomers (e.g., glycopyrrolate bromide used herein which was amixture of R,S and S,R diastereomers), includes any one of the fourdiastereomers listed below as well as any mixture of two, three, or fourof the diastereomers:

-   (R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium    4-methylbenzenesulfonate;-   (S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium    4-methylbenzenesulfonate;-   (R)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium    4-methylbenzenesulfonate; and-   (S)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium    4-methylbenzenesulfonate.

In one embodiment, “glycopyrrolate tosylate” is(R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. In another embodiment, the “glycopyrrolatetosylate” is(S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. In another embodiment, the “glycopyrrolatetosylate” is(R)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. In another embodiment, the “glycopyrrolatetosylate” is(S)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. In yet another embodiment, the “glycopyrrolatetosylate” is a racemic mixture of(R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate and(S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. In yet another embodiment, the “glycopyrrolatetosylate” is a racemic mixture of(R)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate and(S)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. The solvate, such as hydrate, of“glycopyrrolate tosylate”, can be a solvate, e.g., a hydrate, of any oneof the four diastereomers listed above or any mixture of two, three, orfour of the diastereomers. When referencing “threo” glycopyrrolatetosylate, those of ordinary skill will recognize that it refers to amixture of R,S and S, R diastereomers. Thus, threo glycopyrrolatetosylate refers to a racemic mixture of(R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate and(S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate.

It is to be understood that the invention further includes isotopicsubstitution. For example, deuterated glycopyrrolates are includedwithin the definition of glycopyrrolate.

In one embodiment of the disclosure, a salt of glycopyrrolate isprovided wherein the anion is selected from benzoate, edisylate,oxalate, hydrogen sulfate, and tosylate including hydrates and solvatesthereof. In a further embodiment, a solid salt of glycopyrrolate isprovided wherein the anion is selected from benzoate, edisylate,oxalate, hydrogen sulfate, and tosylate including polymorphs, hydrates,solvates, the corresponding amorphous forms of each salt, andco-crystals thereof.

In a further embodiment, a crystalline salt of glycopyrrolate benzoateis provided. An x-ray powder diffraction pattern substantially the sameas the pattern of FIG. 12 may be used to characterize one embodiment ofcrystalline glycopyrrolate benzoate. A smaller subset of the peaks maybe used to characterize crystalline glycopyrrolate benzoate. Forexample, any one or more of the peaks, for example, at about 8.0, 11.8,16.1, 17.8, 18.8, 20.1, or 23.8° 2θ may be used to characterizecrystalline glycopyrrolate benzoate. For example, the peaks at about8.0° 2θ and 16.0° 2θ may be used to characterize glycopyrrolatebenzoate. In another embodiment, a DSC endotherm at about 79° C. asshown in FIG. 13 may be used to characterize crystalline glycopyrrolatebenzoate. Combinations of x-ray data and DSC data may also be used tocharacterize glycopyrrolate benzoate. For example, one or more of thepeaks at about 8.0, 11.8, 16.1, 17.8, 18.8, 20.1, or 23.8° 2θ, such asthe peaks at about 8.0° 2θ and 18.8° 2θ together with a DSC endotherm atabout 79° C. may be used to characterize glycopyrrolate benzoate.

In an additional embodiment, a crystalline salt of di-glycopyrrolateedisylate is provided. An x-ray powder diffraction pattern substantiallythe same as the pattern of FIG. 14 may be used to characterize oneembodiment of crystalline di-glycopyrrolate edisylate. A smaller subsetof the peaks may be used to characterize crystalline di-glycopyrrolateedisylate. For example, any one or more of the peaks, for example, atabout 5.2, 9.2, 10.4, 11.2, 12.9, 15.3, 17.9, 18.6, 20.9, 22.3, or 23.7°2θ may be used to characterize crystalline di-glycopyrrolate edisylate.For example, the peaks at about 11.2 and 17.9° 2θ may be used tocharacterize di-glycopyrrolate edisylate. In another embodiment, a DSCendotherm at about 103° C. as shown in FIG. 15 may be used tocharacterize crystalline di-glycopyrrolate edisylate. Combinations ofx-ray data and DSC data may also be used to characterizedi-glycopyrrolate edisylate. For example, in addition, one or more ofthe peaks at about 5.2, 9.2, 10.4, 11.2, 12.9, 15.3, 17.9, 18.6, 20.9,22.3, or 23.7° 2θ, such as the peaks at about 11.2 and 17.9° 2θ togetherwith a DSC endotherm at about 103° C. may be used to characterizedi-glycopyrrolate edisylate.

In a further embodiment, a crystalline salt of glycopyrrolate oxalate isprovided. An x-ray powder diffraction pattern substantially the same asthe pattern of FIG. 16 may be used to characterize one embodiment ofcrystalline glycopyrrolate oxalate. A smaller subset of the peaks may beused to characterize crystalline glycopyrrolate oxalate. For example,any one or more of the peaks, for example, at about 5.0, 8.4, 10.7, or12.1° 2θ may be used to characterize crystalline glycopyrrolate oxalate.For example, the peaks at about 5.0 and 8.4° 2θ may be used tocharacterize glycopyrrolate oxalate.

In an additional embodiment, a crystalline salt of glycopyrrolatehydrogen sulfate is provided. An x-ray powder diffraction patternsubstantially the same as the pattern of FIG. 17 may be used tocharacterize one embodiment of crystalline glycopyrrolate hydrogensulfate. A smaller subset of the peaks may be used to characterizecrystalline glycopyrrolate hydrogen sulfate. For example, any one ormore of the peaks, for example, at about 5.6, 13.1, 14.5, 17.2, 18.2,19.9, 20.2, 21.4, 21.6, 22.7, or 28.9° 2θ may be used to characterizecrystalline glycopyrrolate hydrogen sulfate. For example, the peaks atabout 5.6 and 13.1° 2θ may be used to characterize glycopyrrolatesulfate. In another embodiment, a DSC endotherm at about 160° C. and/ora second endotherm at about 169° C. as shown in FIG. 18 may be used tocharacterize crystalline glycopyrrolate hydrogen sulfate. Combinationsof x-ray data and DSC data may also be used to characterizeglycopyrrolate hydrogen sulfate. For example, in addition, one or moreof the peaks at about 5.6, 13.1, 14.5, 17.2, 18.2, 19.9, 20.2, 21.4,21.6, 22.7, or 28.9, such as the peaks at about 5.6 and 13.1° 2θ,together with a DSC endotherm at about 160° C. or a second endotherm atabout 169° C. or both may be used to characterize glycopyrrolatehydrogen sulfate.

In a further embodiment, a crystalline salt of glycopyrrolate acetate isprovided. An x-ray powder diffraction pattern substantially the same asthe pattern of FIG. 22 may be used to characterize one embodiment ofcrystalline glycopyrrolate acetate. A smaller subset of the peaks may beused to characterize crystalline glycopyrrolate acetate. For example,any one or more of the peaks, for example, at about 5.2, 10.4, 10.8,11.3, 12.6, 15.4, 17.5, 19.1, or 23.6° 2θ may be used to characterizecrystalline glycopyrrolate acetate. For example, the peaks at about 5.2and 11.3° 2θ may be used to characterize glycopyrrolate acetate.

In another embodiment crystalline glycopyrrolate tosylate monohydrate isprovided, also referred to herein as Form D glycopyrrolate tosylate orForm D or crystalline glycopyrronium tosylate monohydrate. Exemplarypreparations of Form D glycopyrrolate tosylate include Examples 8 and 9herein. The ORTEP drawing of Form D glycopyrrolate tosylate, based onits crystal structure, is set forth in FIG. 1. The chemical structure ofForm D glycopyrrolate tosylate is set forth below as Formula I:

The XRPD pattern corresponding to Form D glycopyrrolate tosylate isrepresented by FIG. 1. The crystal structure of the monoclinic Form Dglycopyrrolate tosylate is set forth herein with the crystal data andacquisition parameter provided in Table 1.

TABLE 1 Crystal Data and Data Collection Parameters for GlycopyrrolateTosylate Form D formula C₂₆H₃₇NO₇S formula weight 507.65 space groupP2₁/n (No. 14) a 8.8715(5) Å b 11.5849(7) Å c 25.5323(14) Å β 96.9 deg V2604.9(3) Å³ Z 4 d_(calc), g cm⁻³ 1.294 crystal dimensions, mm 0.23 ×0.20 × 0.18 temperature, K. 150. radiation (wavelength, Å) Cu K_(α)(1.54184) monochromator confocal optics linear abs coef, mm⁻¹ 1.479absorption correction applied empirical^(a) transmission factors: min,max 0.592, 0.766 diffractometer Rigaku RAPID-II h, k, l range 0 to 10 0to 13 −31 to 30 2θ range, deg 3.49-140.48 mosaicity, deg 0.76 programsused SHELXTL F₀₀₀ 1088.0 weighting 1/[(σ²(F_(o) ²) + (0.1231P)² +0.8250P] where P = (F_(o) ² + 2F_(c) ²)/3 data collected 24514 uniquedata 4024 R_(int) 0.086 data used in refinement 4024 cutoff used inR-factor calculations F_(o) ² > 2.0σ(F_(o) ²) data with I > 2.0σ(I) 3812number of variables 331 largest shift/esd in final cycle 0.00 R(F_(o))0.064 R_(w)(F_(o) ²) 0.185 goodness of fit 1.098 ^(a)Otwinowski, Z.;Minor, W. Methods Enzymol. 1997, 276, 307. ^(b) Flack, H. D. ActaCryst., 1983 A39, 876. ^(c) Hooft, R. W. W., Straver, L. H., and Spek,A. L. J. Appl. Cryst., 2008, 41, 96-103.

Form D glycopyrrolate tosylate was found to be monoclinic with spacegroup P2₁/n. At 150K, the calculated density was found to be 1.294 gramsper cubic centimeter. To two significant figures after the decimal, theunit cell dimensions were determined to be: a equals about 8.87 Å; bequals about 11.58 A; and c equals about 25.53 A, with correspondingunit cell angles of α=90.00°, β=96.9°, and γ=90.00°. The Form D unitcell was found to be racemic with both R,S and S,R diastereomers ofglycopyrrolate in the unit cell.

A pattern substantially the same as the pattern of FIG. 2 may be used tocharacterize Form D glycopyrrolate tosylate. A smaller subset of thepeaks identified in FIG. 2 may instead be used to characterize Form Dglycopyrrolate tosylate. For example, any one or more of peaks at about6.9, 10.3, 12.6, 13.7, 14.9, 15.3, 15.7, 16.4, 17.7, 18.2, or 20.6° 2θmay be used to characterize Form D glycopyrrolate tosylate. For example,the single peak at about 6.9 or 10.3 or 12.6, or 20.6° 2θ may be used tocharacterize Form D glycopyrrolate tosylate. In another example, peaksat about 6.9 and 10.3° 2θ may be used to characterize Form Dglycopyrrolate. In a further example, the peaks at about 6.9, 10.3, and12.6° 2θ may be used to characterize Form D glycopyrrolate tosylate. Instill another example, the peaks at about 10.3 and 12.6° 2θ characterizeForm D glycopyrrolate tosylate. Table 2 identifies selected peaks fromFIG. 2. Intensity is provided for completeness.

TABLE 2 Selected Peaks from FIG. 2 Diffraction angle °(2θ) d spacing (Å)Intensity (%)  6.87 ± 0.20 12.867 ± 0.385 100 10.26 ± 0.20  8.620 ±0.171 16 12.55 ± 0.20  7.052 ± 0.114 85 13.72 ± 0.20  6.454 ± 0.095 1514.91 ± 0.20  5.943 ± 0.080 29 15.31 ± 0.20  5.788 ± 0.076 18 15.68 ±0.20  5.653 ± 0.073 17 16.43 ± 0.20  5.396 ± 0.066 14 17.73 ± 0.20 5.002 ± 0.057 19 18.15 ± 0.20  4.888 ± 0.054 25 18.60 ± 0.20  4.770 ±0.051 53 18.82 ± 0.20  4.716 ± 0.050 28 19.59 ± 0.20  4.532 ± 0.046 1620.21 ± 0.20  4.395 ± 0.043 26 20.62 ± 0.20  4.307 ± 0.042 63 21.09 ±0.20  4.212 ± 0.040 19 21.63 ± 0.20  4.109 ± 0.038 19 23.50 ± 0.20 3.786 ± 0.032 14 25.15 ± 0.20  3.541 ± 0.028 27

Further, Form D glycopyrrolate tosylate is distinguishable from Form Cglycopyrrolate tosylate and the dehydrated form of Form D glycopyrrolatetosylate by the presence of water in the unit cell of Form D and may beso characterized.

Form D glycopyrrolate tosylate may also be characterized by the IRspectrum in FIG. 3. When considering just IR spectroscopy, the entire IRspectrum may be used to characterize Form D glycopyrrolate tosylate or asubset of the spectrum may be so used. For example, any one or more ofpeaks at about 1734, 1196, 1125, 1036, 1013, and 682 cm⁻¹ or others maybe used alone or in combination to characterize Form D glycopyrrolatetosylate. Selected peaks from the IR spectrum in FIG. 3 are set forthbelow in Table 3.

TABLE 3 Selected Peaks in the IR Spectrum of Form D in from FIG. 3 incm⁻¹ 682 1230 703 1265 713 1281 735 1312 750 1320 801 1329 815 1361 8501373 856 1382 880 1445 908 1464 934 1476 940 1488 954 1495 975 1599 10131636 1024 1734 1036 2868 1075 2954 1084 2967 1125 3033 1139 3057 11553422 1182 3568 1196

Form D glycopyrrolate tosylate may be characterized by both the IR andXRPD data as set forth herein. For example, Form D glycopyrrolatetosylate may be characterized by one or more XRPD peaks selected from,for example, about 6.9, 10.3, 12.6, 13.7, 14.9, 15.3, 15.7, 16.4, 17.7,18.2, or 20.6° 2θ and one or more of the IR peaks selected from, forexample, about 1734, 1196, 1125, 1036, 1013, and 682 cm⁻¹.

Form D may be prepared by several methods. In one method, glycopyrrolatebromide is treated with a metal salt such as silver salt, of tosylate toform a glycopyrrolate salt. In particular Form D glycopyrrolate tosylatemay be prepared by treating Ag-tosylate with glycopyrrolate-X in asuitable solvent to form a slurry; removing the solids from the slurryto obtain a solution; lyophilizing the solution to form a solid;dissolving the solid in a crystallization solvent; and removing thecrystallization solvent to form Form D glycopyrrolate tosylate, whereinX is a halide. Suitable solvents are those that will afford a slurrywhen treating Ag-tosylate with glycopyrrolate-X. An example of asuitable solvent is an alcohol such as isopropanol. A crystallizationsolvent is a solvent, or mixtures thereof, which will dissolvesufficient solid provided after the lyophilizing stage such that whenthe crystallization solvent is removed, Form D glycopyrrolate is theresulting solid. An example of a crystallization solvent is a mixture ofacetonitrile and water. Embodiments include where X is a halide such asiodide or bromide.

In some embodiments, the crystallization solvent is removed by loweringthe temperature of the solid obtained after lyophilizing in solution anddecanting the solvent. In these and other embodiments, an anti-solvent,such as toluene, is added to the solution containing the dissolvedsolid.

Form D glycopyrrolate tosylate may also be prepared by treatingglycopyrrolate-Y and p-toluenesulfonic acid in a suitable solvent;removal of the solvent to form a solid; re-dissolving the solid in acrystallization solvent to form a solution and removing thecrystallization solvent to form Form D glycopyrrolate tosylate wherein Yis an organic anion. An example of Y is acetate.

In some embodiments, an anti-solvent, such as toluene, is added to thesolution containing the dissolved solid.

As disclosed in US 20100276329, glycopyrrolate bromide may be used totreat hyperhidrosis such as by using a wipe containing a solution ofglycopyrrolate bromide. It is the glycopyrrolate cation (glycopyrronium)of the bromide salt which is the active clinical moiety becauseglycopyrronium has equivalent binding affinity for the M3 muscarinicacetylcholine receptor in vitro when delivered as either the bromide oranother salt such as the tosylate salt. In one study, patients sufferingfrom hyperhidrosis were treated with formulations containing 2% and 4%glycopyrrolate based on a glycopyrrolate bromide preparation. It wasobserved that axillary sweating was reduced in patients during thisstudy and a dose dependent trend in efficacy responses was alsoobserved. Such dose dependency is consistent with glycopyrrolate'santi-muscarinic activity. Accordingly, glycopyrrolate tosylate may alsobe used to treat hyperhidrosis in patients such as by administering atopical containing glycopyrrolate tosylate. By topical, what is meant isa material or formulation comprising or containing glycopyrrolatetosylate which may be used to deliver glycopyrrolate tosylate, includinga pharmaceutically effective amount of glycopyrrolate tosylate, to apatient. In many embodiments, the glycopyrrolate tosylate is threoglycopyrrolate tosylate. Examples of a topical include, but are notlimited to, solutions, ointments, gels, lotions, powders, sprays,creams, cream bases, patches, pastes, washes, dressings, masks, gauzes,bandages, swabs, brushes, or pads. The application of the topical may becontrolled by controlling the dose amount or the rate of release. Thedose may be controlled by dissolving or dispensing threo glycopyrrolatetosylate, for example, in the appropriate medium. These and other dosecontrolling formulations may be used to deliver controlled doses such asspecific unit doses, metered doses, or multiple doses from the topical.

In one embodiment, the topical is an absorbent pad. In such embodiments,such an absorbent pad may contain another topical such as a solution. Asused herein, absorbent pads and nonwoven wipes are interchangeable andhave the same meaning. In another embodiment, an absorbent padcontaining threo glycopyrrolate tosylate in solution may be used totreat hyperhidrosis. Further, pads or wipes containing one or more ofglycopyrrolate benzoate, edisylate, oxalate, or hydrogen sulfate insolution may similarly be used to treat hyperhidrosis in patients. Inanother embodiment, the pharmaceutically acceptable solution of threoglycopyrrolate tosylate is a topical.

In another embodiment, crystalline glycopyrrolate tosylate anhydrate isdisclosed, also referred to herein as Form C glycopyrrolate tosylate orForm C. Exemplary preparations of Form C glycopyrrolate tosylate includeExamples 11, 12, and 13 herein.

The x-ray powder diffraction pattern corresponding to Form Cglycopyrrolate tosylate is provided in FIG. 4. The infrared spectrumcorresponding to Form C glycopyrrolate tosylate is provided in FIG. 5.Form C was indexed to determine unit cell dimensions and the indexingsolution is presented as FIG. 6.

An x-ray powder diffraction pattern substantially the same as thepattern of FIG. 4 may be used to characterize Form C glycopyrrolatetosylate. A smaller subset of the peaks identified in FIG. 4 may be usedto characterize Form C glycopyrrolate tosylate. For example, any one ormore of the peaks at about 5.5, 11.0, 11.8, 13.9, 14.9, 17.8, 19.6,20.4, 21.6 and 22.1° 2θ may be used to characterize Form Cglycopyrrolate tosylate. For example, the single peaks at about 5.5 or11.0 or 14.9° 2θ may be used to characterize Form C glycopyrrolatetosylate, or any combination of the three. In another example, peaks atabout 5.5 and 11.0° 2θ may be used to characterize Form Cglycopyrrolate. In a further example, the peaks at about 5.5, 11.0, and14.9° 2θ may be used to characterize Form C glycopyrrolate tosylate.Table 4 identifies selected peaks from FIG. 4. Further, Form Cglycopyrrolate tosylate is distinguishable from Form D glycopyrrolatetosylate since Form C lacks water in the unit cell. Intensity isprovided for completeness.

TABLE 4 Selected Peaks from FIG. 4 Diffraction angle °(2θ) d spacing (Å)Intensity (%)  5.47 ± 0.20 16.168 ± 0.614 100 10.98 ± 0.20  8.057 ±0.149 34 11.82 ± 0.20  7.489 ± 0.128 13 13.87 ± 0.20  6.384 ± 0.093 2014.86 ± 0.20  5.963 ± 0.081 82 17.75 ± 0.20  4.997 ± 0.056 67 17.92 ±0.20  4.951 ± 0.055 53 18.12 ± 0.20  4.897 ± 0.054 35 19.60 ± 0.20 4.528 ± 0.046 51 20.39 ± 0.20  4.356 ± 0.043 42 21.59 ± 0.20  4.116 ±0.038 27 22.14 ± 0.20  4.014 ± 0.036 26

Form C glycopyrrolate tosylate may also be characterized by the IRspectrum in FIG. 5. When considering just IR spectroscopy, the entire IRspectrum may be used to characterize Form C glycopyrrolate tosylate or asubset of the spectrum may be so used. For example, any one or more ofthe peaks at about 1733, 1236, 1211, 1198, 1186, 1177, 1120, 1032, 1008,and 682 cm⁻¹ or others may be used alone or in combination tocharacterize Form C glycopyrrolate tosylate. Selected peaks from the IRspectrum in FIG. 5 are set forth below in Table 5.

TABLE 5 Selected Peaks from FIG. 5 in cm⁻¹ 682 1120 706 1177 714 1186742 1198 755 1211 786 1236 801 1293 821 1317 849 1446 886 1464 929 1475938 1485 956 1597 980 1733 1008 2867 1032 2961 1075 3032

Form C glycopyrrolate tosylate may be characterized by both the IR andXRPD data as set forth herein. For example, Form C glycopyrrolatetosylate may be characterized by one or more XRPD peaks selected from,for example, about 5.5, 11.0, 11.8, 13.9, 14.9, 17.8, 19.6, 20.4, 21.6,and 22.1° 2θ and one or more of the IR peaks selected from, for example,1733, 1236, 1211, 1198, 1186, 1177, 1120, 1032, 1008, and 682 cm⁻¹.

Form C may also be characterized by its thermal characteristics. Forexample, Form C exhibits a melting endotherm at about 168° C. whenmeasured with a Tzero™ pan type configuration at a heating rate of 10°C. per minute from −30° C. to 250° C.

Form C may be characterized by its DSC thermogram alone or incombination with the x-ray powder diffraction data, IR data, or both.For example, Form C glycopyrrolate tosylate may be characterized by aDSC thermogram having an endotherm at about 168° C. and the x-ray powderdiffraction pattern of FIG. 4 and the IR spectrum of FIG. 5. However, itis not necessary to use all of these data to characterize Form C whenusing DSC. For example, the single peak at about 5.5° 2θ and the DSCendotherm at about 168° C. may be used to characterize Form Cglycopyrrolate tosylate (see FIG. 7). In another example, the peak atabout 168° C. and the IR peak at about 1733 cm⁻¹ may be used tocharacterize Form C glycopyrrolate tosylate. In yet another example, theendotherm at 168° C., the x-ray powder diffraction peak at about 5.5°2θ, and the IR peak at about 1733 cm⁻¹ may be used to characterize FormC glycopyrrolate tosylate.

Form C may be prepared by dehydrating Form D. Alternatively, Form C maybe prepared by dissolving a glycopyrrolate salt such as, for example, atelevated temperatures such as about 50° C. Slow cooling of the solutionto room temperature followed by vacuum filtration and washing in asuitable organic solvent such as acetone results in the formation ofForm C.

In a further embodiment, dehydrated forms of Form D are provided. Anexemplary preparation of dehydrated Form D includes Example 10 herein.In one such embodiment, a dehydrated form of Form D, hereinafterreferred to as dehydrated Form D, is provided wherein there is no waterin the unit cell. An x-ray powder diffraction pattern of dehydrated FormD is provided in FIG. 8. An overlay of the diffraction pattern showingdehydrated Form D and Form D is provided in FIG. 9.

The indexing solution, with a Pawley refinement, to dehydrated Form D ispresented in FIG. 10 and indicates a unit cell which is of the sameproportions, within experimental variation, as with the indexingsolution of Form D, also with a Pawley refinement (FIG. 11) except for aloss of volume, which is consistent with water loss, and which resultsin a smaller unit cell. The indexing solution from FIG. 11 presents a,b, and c parameters which correspond, respectively, to the c, b, and aparameters of the single crystal study (performed at 150 K) as set forthin Table 1.

The overlay pattern from Form D and dehydrated Form D show that thereare some shifts between the two forms and that can also be seen in thecomparison of the peak positions for selected Miller indices as setforth in Table 6 below. The differences in the Miller indices betweenForm D and dehydrated Form D confirm that they are different solidforms.

TABLE 6 Select Miller Indices and Peak Comparisons between Form D andDehydrated Form D h k l Form D (2⊖) Dehydrated (2⊖) Δ 2 0 0 6.848736.74897 −0.09976 1 1 0 8.16348 8.21407 0.05059 2 1 0 10.09605 10.08663−0.00942 1 0 −1 10.22338 10.50517 0.28179 1 0 1 11.02323 11.370500.34727 0 1 1 12.50656 12.83560 0.32904 1 −1 −1 12.63742 12.91262 0.27522 0 2 22.15015 22.85492 0.70477 1 1 2 22.21449 22.92323 0.70874

Dehydrated Form D is further distinguishable from Form D since it lackswater of crystallization whereas Form D is a monohydrate and from Form Cbecause the peaks of dehydrated Form D (an anhydrate) differsubstantially from those in Form C (anhydrate). For example, as Table 6indicates, dehydrated Form D has a peak at about 6.75° 2θ whereas theclosest peak from Form C is at about 6.30° 2θ, a difference of 0.45° 2θ.In addition, the indexing solution for Form C shows the unit cell to betriclinic whereas the unit cell of dehydrated Form D is monoclinic.

In another series of embodiments, variable hydrates, each with differentwater content in between dehydrated Form D and monohydrate Form D isprovided. Such embodiments provide for a continuum of water content inbetween dehydrated Form D and Form D as illustrated with one example inFIG. 9. One would expect that other materials with an intermediate watercontent to generally exhibit x-ray powder diffraction pattern yieldingpeaks which are intermediate between Form D and dehydrated Form D.

In a further embodiment, the amorphous glycopyrrolate tosylate has anx-ray powder diffraction pattern exhibiting a figure substantially thesame as FIG. 19. In another embodiment, the amorphous glycopyrrolatetosylate of the invention has a glass transition temperature onset ofabout 11.6° C. In yet another embodiment, the amorphous glycopyrrolatetosylate of the invention has an x-ray powder diffraction patternsubstantially the same as in FIG. 19 and a glass transition onsettemperature of about 11.6° C. In still an additional embodiment, theamorphous glycopyrrolate tosylate of the invention has an x-ray powderdiffraction pattern exhibiting an amorphous halo but that is notsubstantially similar to that of FIG. 19.

The amorphous glycopyrrolate tosylate of the invention was observed tobe amorphous by X-ray diffraction in that it had contained the“amorphous halo” associated with amorphous solids. Such a material isoften called “x-ray amorphous.” As used herein, “amorphous” whendescribing glycopyrrolate tosylate means amorphous as determined byx-ray powder diffraction such as, for example, as shown in FIG. 19. DSCand thermogravimetric data for an x-ray amorphous form are shown in FIG.20 whereas the modulated DSC thermogram is set forth in FIG. 23.

Amorphous glycopyrrolate tosylate was found to be extremely hygroscopicwhich deliquesced readily when exposed to standard atmosphericconditions. In addition, the extremely low glass transition renders theamorphous form of glycopyrrolate challenging to formulate successfully.However, applicants have been able to raise the glass transitiontemperature, and reduce the likelihood of deliquescence by preparingsolid dispersions of glycopyrrolate tosylate.

Solid dispersions can be prepared in a number of different methods knownin the art including lyophilization and spray drying. The soliddispersions herein were all created by lyophilization. The soliddispersions prepared herein are set forth in the Examples and may beprepared by combining a solution of glycopyrrolate tosylate with asolution of an excipient in one or more solvents where both componentsare soluble. The solutions may be filtered and are then cooled so thatthe solutions freeze. After freezing, the solutions are dried, such asin a lyophilizer, so as to form dispersions. The presence of a soliddispersion can be verified by comparing, for example, spectra of thestarting materials with the purported dispersion or by observing a glasstemperature different than either of the components. A mixture would beevident by a simply linear combination of the peaks of the two startingmaterials whereas in a dispersion, peak shifts indicate the preparationof a different material, namely, a solid dispersion. A solid dispersionis also evident by the presence of a single glass transitiontemperature.

A solid dispersion comprising glycopyrrolate tosylate and excipientsincluding monosaccharides, disaccharides, and pharmaceuticallyacceptable polymers containing cyclic ether moieties may be formed undersuitable conditions such as by lyophilization. In some embodiments, suchsolid dispersions have a glass transition temperature of at least about25° C. including at least about 40° C. and at least about 60° C. Inthese and other embodiments, the weight ratio of sucrose toglycopyrrolate tosylate is about 9:1. In other embodiments, the cyclicethers are six-membered rings, such as in hypromellose acetate succinate(HPMCAS) and such solid dispersions have a glass transition temperatureof at least about 25° C. including at least about 40° C. and at leastabout 60° C. In these and other embodiments, the weight ratio of HPMCASto glycopyrrolate tosylate is about 1:1.

A solid dispersion comprising glycopyrrolate tosylate and excipientsincluding pharmaceutically acceptable polymers containing polyethyleneglycol moieties such as a polyvinyl alcohol-polyethylene glycol graftcopolymer, such as Kollicoat® IR, or a polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer, such as Soluplus®, may beformed under suitable conditions such as by lyophilization. In someembodiments, such solid dispersions have a glass transition temperatureof at least about 30° C. including at least about 40° C.

A solid dispersion comprising glycopyrrolate tosylate and excipientsincluding pharmaceutically acceptable polymers containing vinylpyrrolidone moieties such as polyvinyl pyrrolidone or vinylpyrrolidone-vinyl acetate copolymer may be formed under suitableconditions such as by lyophilization. In some embodiments, such soliddispersions have a glass transition temperature of at least about 25° C.including at least about 35° C. and further including about 60° C.Examples of polyvinyl pyrrolidone polymers used herein include PVPK29/32 and PVP K90. Examples of a vinyl pyrrolidone-vinyl acetatecopolymer used herein include Kollidon® VA 64.

As used herein, the term “a pharmaceutically acceptable polymer” means apolymer approved for use in humans in pharmaceutical formulationsincluding those polymers not yet approved but for whom approval ispending.

HPMCAS may be used to form a solid dispersion with glycopyrrolatetosylate in, for example, a ratio of about 1 to 1 of HPMCAS toglycopyrrolate by weight. An example of such a preparation can be foundin Example 19. FIG. 24 is an overlay infrared spectrum of a region ofthe spectrum showing differences between the dispersion and thecomponent parts. For example, there is a peak at about 1211 cm⁻¹ in theglycopyrrolate tosylate spectrum and a peak at about 1235 cm⁻¹ in theHPMCAS spectrum. By comparison, in the solid dispersion spectrum, asingle peak appears at about 1228 cm⁻¹ indicating the material is not aphysical mixture. This is confirmed with FIG. 25 which shows a singleglass transition temperature (also sometimes referred to as Tg) at about42° C.

The solid 1:1 dispersion of HPMCAS and glycopyrrolate tosylate may becharacterized by either its infrared spectrum, glass transitiontemperature or both. For example, a 1:1 solid dispersion ofHPMCAS:glycopyrrolate tosylate may be characterized by a peak at about1228 cm⁻¹, a glass transition temperature of about 42° C., or both.

Sucrose may be used to form a solid dispersion with glycopyrrolatetosylate in, for example, a ratio of about 9 to 1 of sucrose toglycopyrrolate by weight. An example of such a preparation can be foundin Example 20. FIG. 26 shows a single glass transition temperature atabout 62° C. confirming the presence of a solid dispersion. This glasstransition temperature may be used to characterize the dispersion.

A polyvinyl alcohol-polyethylene glycol copolymer may be used to form asolid dispersion with glycopyrrolate tosylate, in, for example, ratiosof between about 1:1 and 9:1. An example of the 1:1 dispersionpreparation can be found in Example 21 and a 9:1 dispersion in Example22. FIGS. 27 a and 27 b are overlay infrared spectra of two regions ofthe spectrum showing differences between the 1:1 dispersion and thecomponent parts. For example, there are peaks at about 1107 cm⁻¹ and1322 cm⁻¹ in the glycopyrrolate tosylate spectrum and peaks at about1092 cm⁻¹ and 1331 cm⁻¹ in the polyvinyl alcohol-polyethylene glycolcopolymer spectrum. By comparison, in the solid dispersion spectrum, asingle peak now appears at about 1099 cm⁻¹ and 1324 cm⁻¹ respectivelyindicating the material is not a physical mixture. This is confirmedwith FIG. 28 which shows a single glass transition temperature (Tg) atabout 32° C. FIG. 29 shows a single glass transition temperature of the9:1 dispersion to be at about 35° C.

The 1:1 solid dispersion of a polyvinyl alcohol-polyethylene glycolcopolymer and glycopyrrolate tosylate may be characterized by itsinfrared spectrum, glass transition temperature, or both. For example,one or more peaks in the infrared spectrum of the dispersion at about1099 cm⁻¹ and 1324 cm⁻¹, a glass transition temperature at about 32° C.,or a combination thereof may be used to characterize the soliddispersion. The 9:1 solid dispersion may be characterized by a glasstransition temperature at about 35° C.

A polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graftcopolymer may be used to form a solid dispersion with glycopyrrolatetosylate in, for example, a ratio of about 1 to 1 of the polymer toglycopyrrolate by weight. An example of such a preparation can be foundin Example 23. FIGS. 30 a, 30 b, and 30 c are overlay infrared spectraof regions of the spectrum showing differences between the dispersionand the component parts. For example, there are peaks at about 938 cm⁻¹,about 1190 cm⁻¹, and about 1448 cm⁻¹ in the glycopyrrolate tosylatespectrum and peaks at about ¹ and 947 cm⁻¹, about 1197 cm⁻¹, and about1442 cm⁻¹ in the polyvinyl caprolactam-polyvinyl acetate-polyethyleneglycol graft copolymer spectrum. By comparison, in the solid dispersionspectrum, a single peak appears at about 942 cm⁻¹, about 1195 cm⁻¹, andabout 1445 cm⁻¹ respectively indicating the material is not a physicalmixture. This is confirmed with FIG. 31 which shows a single glasstransition temperature at about 40° C.

The solid 1:1 dispersion of a polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer and glycopyrrolate tosylatemay be characterized by either its infrared spectrum, glass transitiontemperature or both. For example, a 1:1 solid dispersion of a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graftcopolymer:glycopyrrolate tosylate may be characterized by one or morepeaks at about 942 cm⁻¹, about 1195 cm⁻¹, or about 1445 cm⁻¹, a glasstransition temperature of about 40° C., or a combination thereof.

A polyvinyl pyrrolidone polymer may be used to form a solid dispersionwith glycopyrrolate tosylate in, for example, a ratio of about 1 to 1 ofthe polymer to glycopyrrolate by weight or a ratio of about 8 to 1 byweight. An example of such a preparation can be found in Examples 24, 25and 26. FIGS. 32 a, 32 b, and 32 c are overlay infrared spectra ofregions of the spectrum showing differences between the dispersion andthe component parts for Example 24. For example, there are peaks atabout 1283 cm⁻¹ and 1651 cm⁻¹ in the glycopyrrolate tosylate spectrumand peaks at about 1294 cm⁻¹, about 1465 cm⁻¹, and about 1641 cm⁻¹ inthe polyvinyl pyrrolidone spectrum of Example 24. By comparison, in thesolid dispersion spectrum, peaks occur at about 1288 cm⁻¹, about 1461cm⁻¹, and about 1664 cm⁻¹ respectively indicating the material is not aphysical mixture. Further, the dispersion exhibits a peak at about 1438cm⁻¹, which has no counterpart peaks in either the polymer or theglycopyrrolate tosylate. In addition, FIG. 33 indicates a soliddispersion showing a single glass transition temperature at about 38° C.for the dispersion of Example 24. The 8:1 dispersion of Example 25 showsa single glass transition temperature of about 26° C. as seen in FIG.34.

The 1:1 solid dispersion using the polyvinyl pyrrolidone of Example 24may be characterized by its infrared spectrum, glass transitiontemperature, or both. For example, it may be characterized by one ormore peaks in the infrared spectrum at 1288 cm⁻¹, about 1461 cm⁻¹, about1664 cm⁻¹, or about 1438 cm⁻¹, a glass transition temperature of about38° C., or a combination thereof. The 8:1 solid dispersion using thepolymer of Example 25 may be characterized by a glass transitiontemperature of about 26° C.

The polyvinyl pyrrolidone of Example 26 was used to prepare anapproximately 1 to 1 solid dispersion of polyvinyl pyrrolidone toglycopyrrolate tosylate. FIG. 32 d is an overlay infrared spectrum of aregion of the spectrum showing differences between the dispersion andthe component parts. For example, there is a peak at about 1650 cm⁻¹ inthe glycopyrrolate tosylate spectrum and a peak at about 1658 cm⁻¹ inthe polyvinyl pyrrolidone spectrum. By comparison, in the soliddispersion spectrum, a single peak appears at about 1664 cm⁻¹ indicatingthe material is not a physical mixture. This is confirmed with FIG. 35which shows a single glass transition temperature at about 36° C.

The solid 1:1 dispersion of a polyvinyl pyrrolidone polymer of Example26 and glycopyrrolate tosylate may be characterized by either itsinfrared spectrum, glass transition temperature or both. For example,the solid dispersion may be characterized by a peak at about 1664 cm⁻¹ aglass transition temperature of about 36° C., or both.

A vinyl pyrrolidone-vinyl acetate copolymer may be used to form a soliddispersion with glycopyrrolate tosylate in, for example, a ratio ofabout 1 to 1 of a compound of the copolymer to glycopyrrolate by weight.An example of such a preparation can be found in Example 27. FIGS. 36 a,36 b, and 36 c are overlay infrared spectra of regions of the spectrumshowing differences between the dispersion and the component parts. Forexample, there are peaks at about 1381 cm⁻¹, 1300 cm⁻¹, 1283 cm⁻¹, and1651 cm⁻¹ in the glycopyrrolate tosylate spectrum and peaks at about1377 cm⁻¹, 1293 cm⁻¹, and 1641 cm⁻¹ in the copolymer spectrum. Bycomparison, in the solid dispersion spectrum, a single peak appears atabout 1371 cm⁻¹, 1287 cm⁻¹, and 1673 cm⁻¹ respectively, indicating thematerial is not a physical mixture. This is confirmed with FIG. 37 whichshows a glass transition temperature at about 64° C.

The solid 1:1 dispersion of a compound of a vinyl pyrrolidone-vinylacetate copolymer and glycopyrrolate tosylate may be characterized byeither its infrared spectrum, glass transition temperature or both. Forexample, a 1:1 solid dispersion of vinyl pyrrolidone-vinyl acetatecopolymer glycopyrrolate tosylate may be characterized by one or morepeaks at about 1371 cm⁻¹, 1287, and 1673 cm⁻¹, a glass transitiontemperature of about 64° C., or a combination thereof.

Threo glycopyrrolate tosylate may be prepared by treating racemiccyclopentylmandelic acid with racemic 1-methylpyrrolidin-3-ol and 1,1′carbonyldiimidazole in a suitable solvent, such as an organic solvent,to form glycopyrrolate base; treating the glycopyrrolate base in asuitable solvent, such as an alcohol, with a resolving acid to form asalt of threo glycopyrrolate; treating the salt of the threoglycopyrrolate salt with a suitable base in a suitable solvent, such asa mixture of organic solvents and water, to form a threo glycopyrrolatebase; and treating the threo glycopyrrolate base with p-toluenesulfonicacid methyl ester, also known as methyl tosylate or methyl4-benzenesulfonate in a suitable solvent, such as an organic solvent, toform threo glycopyrrolate tosylate. Subsequent treatment as disclosedherein may then be used to prepare, for example, Forms C, D, dehydratedD, or amorphous glycopyrrolate tosylate. In the case of Form D, suchfurther treatment may include recrystallization in water. Care should begiven when working with tosylate compounds since it is known in the artthat aryl sulfonic acids, for example tosylic acid, may react withalcohols to form sulfonate esters, which are alkylating agents. Further,the equilibrium of the reaction is so surprisingly significantlydisplaced toward the dissociated tosylate anion that, even after spikingsuch a low amount as 1 ppm of ethyl tosylate into a 3% threoglycopyrrolate tosylate formulation, the ethyl tosylate levels diminishover time under long-term (25° C./60% relative humidity) and accelerated(40° C./75% relative humidity) stability conditions and are no longerdetectable within weeks of the spike.

Suitable solvents for the preparation of the glycopyrrolate base includethose where the cyclopentylmandelic acid, 1-methylpyrrolidin-3-ol and1,1′ carbonyldiimidazole are soluble such as toluene. The resolving acidis chosen so that the glycopyrrolate base formed, which is a mixture offour isomers, when treated with the resolving acid results in a saltwhich produces substantially the threo pair of isomers. The resolvingacid may be dissolved in solvents such as an alcohol with one examplebeing methanol. This reaction relies on the different solubilities ofthe salts produced. One such resolving acid is 5-Nitroisophthalic acidand it may be dissolved in methanol. Suitable bases for forming thethreo glycopyrrolate base from the salt of the threo glycopyrrolate baseand the resolving acid include hydroxides such as sodium hydroxide andsuch treatment may be done in a mixture of, for example, toluene andwater. Treatment of the resulting base with p-toluenesulfonic acidmethyl ester results in the desired threo glycopyrrolate tosylate.Suitable solvents include acetone and ethyl acetate. Waterrecrystallizations may then be used to form Form D of glycopyrrolatetosylate monohydrate. In some embodiments, seeding with Form D mayassist in the formation of Form D. The Form D may then be dried in someembodiments. A general scheme for the synthesis of threo glycopyrrolatetosylate can be found in Scheme 1 which shows the ultimate formation ofForm D.

In another embodiment, the present invention provides threoglycopyrrolate tosylate in a topical which is not a solution such asointment or a cream. An example of such a cream would be cetomacrogolcream. In another embodiment, the topical is a gel.

In one embodiment, the topical comprises threo glycopyrrolate tosylate.In some of these embodiments, the topical further comprises buffersand/or may be in an aqueous solution. When buffers are used, saidbuffers may be, for example, citric acid and sodium citrate. Thebuffered topical may further comprise an alcohol such as ethanol.

In another embodiment, the present invention provides a pharmaceuticallyacceptable solution comprising threo glycopyrrolate tosylate or asolvate thereof and one or more pharmaceutically acceptable additives.Such additives may include such co-solvents as ethanol and one or morepharmaceutically acceptable excipients.

In another embodiment, the pharmaceutically acceptable solutioncomprising threo glycopyrrolate tosylate or a solvate thereof is aqueousand further comprises one or more buffers. In many embodiments, thepharmaceutically acceptable solution is aqueous. Examples of buffersinclude, but are not limited to citric acid and sodium citratedihydrate. The citric acid includes anhydrous citric acid. The solutionmay also contain one or more alcohols such as ethanol. Dehydratedethanol is an alcohol that may be used. In one embodiment of theinvention, the pharmaceutically acceptable aqueous solution comprisingglycopyrrolate tosylate comprises about 0.15% by weight anhydrous citricacid, about 0.06% sodium citrate dihydrate by weight, between about 57to about 59.5% by weight of dehydrated ethanol, and between about 1% andabout 6% by weight glycopyrrolate tosylate.

In yet another embodiment, the topical is prepared so as to befilm-forming. In such embodiments, a binding agent used. Examples ofbinding agents include povidones such as povidone K90. Such film-formingsolutions further comprise one or more film-forming agents. Examples offilm forming agents include butyl esters of apolyvinylmethylether/maleic anhydride acid copolymer. An example of sucha film forming agent is the Gantrez™ ES-425 butyl ester copolymer

In yet another embodiment, the aqueous pharmaceutically acceptablesolution is prepared so as to be film-forming. In such embodiments, abinding agent used. Examples of binding agents include povidones such aspovidone K90. Such film-forming solutions further comprise one or morefilm-forming agents. Examples of film forming agents include butylesters of a polyvinylmethylether/maleic anhydride acid copolymer. Anexample of such a film forming agent is the Gantrez™ ES-425 butyl estercopolymer.

In some embodiments, the pharmaceutically acceptable solution isabsorbed onto a carrier. For example, such a carrier may be a pad suchas an absorbent pad or nonwoven wipe suitable for holding such solutionwhen in storage as well as for application of the solution to desiredareas of skin.

According to the present invention, the absorbent pad can be based oncotton fabric or non-cotton fabric. In one embodiment, the absorbent padis based on synthetic nonwoven fabric, such as nonwoven rayon andpolypropylene fabric. In one embodiment, the absorbent pad is a 75:25rayon and polypropylene pad.

In some embodiments the absorbent pad material comprises polypropylene.In other embodiments, the absorbent pad is substantially allpolypropylene and in others, the pad is 100% polypropylene. Such padsmay be nonwoven fabric with the following characteristics:

TABLE 7 Pad Properties Physical Property Characteristics Basis Weight 1.231-1.254 ounces/yard² Machine Direction Grab Tensile 15.495-18.862lbf (pounds-force) Cross Direction Grab Tensile 14.425-16.190 lbf FiberDenier  2.443-2.569 dpf (denier per filament)

The pH of a topical such as a solution of glycopyrrolate tosylate,absorbed onto a pad is between 3.5 and 5.5 and often between about 4.0and 5.0, including about 4 to 4.7 and about 4.1 to 4.6. For aglycopyrrolate tosylate monohydrate topical such as for a pad, theamount of glycopyrrolate tosylate monohydrate solution used in a pad istypically between about 2 g and 4 g including about 2.8 g or otherpharmaceutically acceptable amounts.

A topical such as a solution may contain varying weight percents ofglycopyrrolate tosylate such as glycopyrrolate tosylate monohydrate. Insome embodiments, the weight percent of the glycopyrrolate tosylate,such as glycopyrrolate tosylate monohydrate, is between about 1% andabout 4%, including between 1.25% and about 4%, including between 2.5%and 3.75% and including each of about 1.25%, 2.5% and about 3.75%. Theweight percents of glycopyrrolate tosylate, including glycopyrrolatetosylate monohydrate, may also be expressed in glycopyrronium weightpercent only. For these weight percents, the weight percents may varybetween about 0.6% and about 3.2%, including between about 1.6% andabout 2.4% and including each of about 0.6%, 1.6% and about 2.4%. Theseweights are readily converted into weight percents of Form D. Forexample, 1.6% of glycopyrronium ion translates into 2.5% of Form D. Theglycopyrrolate tosylate in any of the embodiments wherein they areabsorbed onto the pads or are contained or comprised within the othertopicals may be threo glycopyrrolate tosylate. The topicals such as theabsorbent pad containing a pharmaceutically acceptable solution can beapplied to the area of the body to be treated.

Processes for making aqueous solutions of glycopyrrolate tosylateinclude treating solid glycopyrrolate tosylate in solution with water soas to dissolve the solid glycopyrrolate tosylate in solution. One mayalso add one or more buffers and/or alcohol, to the solution. Thesolution so obtained may then be wetted onto an absorbent pad so that apharmaceutically acceptable amount of glycopyrrolate tosylate has beenabsorbed onto the pad. The alcohol may be ethanol such as dehydratedethanol. The buffers may be citric acid and sodium citrate. In someembodiments, the glycopyrrolate tosylate or a solvate to be dissolved isin a crystalline form. Examples of such crystalline forms include Form Cor Form D. In some embodiments, the glycopyrrolate tosylate or a solvatethereof is in an x-ray amorphous form. In other embodiments, padscontaining a pharmaceutically acceptable aqueous solution ofglycopyrrolate tosylate made by such processes are provided. The wettingmay be done while the pad is in a pouch. In many embodiments, the pouchis heat-sealed after wetting. A typical pouch material is laminatecontaining aluminum foil as a layer. The glycopyrrolate tosylate of theprocesses herein may be threo glycopyrrolate tosylate.

In another embodiment, a pharmaceutically acceptable aqueous solution ofglycopyrrolate tosylate may be prepared by dissolving glycopyrrolatetosylate in a mixture of water with ethanol. One or morepharmaceutically acceptable excipients can be added either prior to orafter the addition of the glycopyrrolate tosylate or a solvate thereofand the aqueous solvent. Said glycopyrrolate tosylate may be threoglycopyrrolate tosylate.

The pharmaceutically acceptable solution of glycopyrrolate tosylate or asolvate thereof is therapeutically useful. For example, thepharmaceutically acceptable solution can be used for treatinghyperhidrosis or reducing sweating in mammals. The pharmaceuticallyacceptable solution is typically applied from a pad on which thesolution is absorbed. In one embodiment, the present invention providesa method of treating hyperhidrosis in a mammal by topicallyadministering to the skin of the mammal a therapeutically effectiveamount of a pharmaceutically acceptable solution of glycopyrrolatetosylate or a solvate thereof. In one embodiment, the mammal is a human.The pharmaceutically acceptable solution can be applied to one orseveral areas or even the whole body including, but not limited to, thehands, e.g., palms; axillae; feet, e.g., soles; groin; face, e.g.,cheeks and forehead; and trunk, e.g., back and abdomen, or scalp. Insome embodiments, methods of treating primary axillary hyperhidrosiswith glycopyrrolate tosylate or a solvate thereof comprising topicallyadministering a therapeutically effective amount of an aqueousglycopyrrolate tosylate solution to the skin of a mammal in needthereof. In many embodiments, such administration may be with anabsorbent pad. In other embodiments, methods of treating palmar orplantar hyperhidrosis with glycopyrrolate tosylate or a solvate thereofare provided. Dosing of glycopyrrolate tosylate may be daily. Saidpharmaceutically acceptable solution of glycopyrrolate tosylate may bethreo glycopyrrolate tosylate.

Instrumental Techniques Used in the Examples

X-ray Powder Diffraction (XRPD)

X-ray Powder Diffraction (XRPD)—Reflection Geometry

XRPD patterns were collected with a PANalytical X'Pert PRO MPDdiffractometer using an incident beam of Cu Kα radiation produced usinga long, fine-focus source and a nickel filter. The diffractometer wasconfigured using the symmetric Bragg-Brentano geometry. Prior to theanalysis, a silicon specimen (NIST SRM 640d) was analyzed to verify theobserved position of the Si 111 peak is consistent with theNIST-certified position. A specimen of the sample was prepared as athin, circular layer centered on a silicon zero-background substrate.Antiscatter slits (SS) were used to minimize the background generated byair. Soller slits for the incident and diffracted beams were used tominimize broadening from axial divergence. Diffraction patterns werecollected using a scanning position-sensitive detector (X'Celerator)located 240 mm from the sample and Data Collector software v. 2.2b. Thedata acquisition parameters for each pattern were: Cu (1.54059 Å) x-raytube, 45 kV voltage, 40 mA amperage, 3.50-40.00° 2θ scan range, 0.017 or0.08° 2θ step size, 1835-1947 s collection time, 1.1 or 1.2°/min scanspeed, ⅛° divergence slit (DS), ¼° incident-beam antiscatter slit (SS),0.0 null revolution time.

X-Ray Powder Diffraction (XRPD)—Transmission Geometry

XRPD patterns were collected with a PANalytical X'Pert PRO MPDdiffractometer using an incident beam of Cu radiation produced using anOptix long, fine-focus source. An elliptically graded multilayer mirrorwas used to focus Cu Kα x-rays through the specimen and onto thedetector. Prior to the analysis, a silicon specimen (NIST SRM 640d) wasanalyzed to verify the observed position of the Si 111 peak isconsistent with the NIST-certified position. A specimen of the samplewas sandwiched between 3-μm-thick films and analyzed in transmissiongeometry. A beam stop, short antiscatter extension, and antiscatterknife edge were used to minimize the background generated by air. Sollerslits for the incident and diffracted beams were used to minimizebroadening from axial divergence. Diffraction patterns were collectedusing a scanning position-sensitive detector (X'Celerator) located 240mm from the specimen and Data Collector software v. 2.2b. The dataacquisition parameters for each pattern were: Cu (1.54059 Å) x-ray tube,45 kV voltage, 40 mA amperage, 1.0-39.99° 2θ scan range, 0.017° 2θ stepsize, 717-721 s collection time, 3.3 or 3.2°/min scan speed, ½°divergence slit (DS), null incident-beam antiscatter slit (SS), 1.0 nullrevolution time.

Variable Temperature X-Ray Powder Diffraction (VT-XRPD)

XRPD patterns were collected with a PANalytical X'Pert PRO MPDdiffractometer using an incident beam of Cu Kα radiation produced usinga long, fine-focus source and a nickel filter. The diffractometer wasconfigured using the symmetric Bragg-Brentano geometry. Data werecollected and analyzed using Data Collector software v. 2.2b. Prior tothe analysis, a silicon specimen (NIST SRM 640d) was analyzed to verifythe Si 111 peak position. A specimen of the sample was packed into anickel-coated copper well. Antiscatter slits (SS) were used to minimizethe background generated by air scattering. Soller slits for theincident and diffracted beams were used to minimize broadening fromaxial divergence. Diffraction patterns were collected using a scanningposition-sensitive detector (X'Celerator) located 240 mm from thesample. The data acquisition parameters for each pattern were: Cu(1.54059 Å) x-ray tube, 45 kV voltage, 40 mA amperage, 3.50-26.00° 2θscan range, 0.008° 2θ step size, 1869 s collection time, 0.7°/min scanspeed, ⅛° divergence slit (DS), ¼° incident-beam antiscatter slit (SS),0.0 null revolution time.

An Anton Paar TTK 450 stage was used to collect in situ XRPD patterns atnon-ambient temperatures. The sample was heated with a resistance heaterlocated directly under the sample holder, and the temperature wasmonitored with a platinum 100 resistance sensor located directly underthe specimen. The power to the heater was supplied and controlled by anAnton Paar TCU 100 interfaced with Data Collector.

Infrared Spectroscopy (IR)

IR spectra were acquired on Nicolet 6700 Fourier transform infrared(FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glomid/far IR source, an extended range potassium bromide (KBr)beamsplitter, and a deuterated triglycine sulfate (DTGS) detector.Wavelength verification was performed using NIST SRM 1921b(polystyrene). An attenuated total reflectance (ATR) accessory(Thunderdome™, Thermo Spectra-Tech), with a germanium (Ge) crystal wasused for data acquisition. Each spectrum represents 256 co-added scanscollected at a spectral resolution of 2 cm-1. A background data set wasacquired with a clean Ge crystal. A Log 1/R (R=reflectance) spectrum wasobtained by taking a ratio of these two data sets against each other.

Differential Scanning Calorimetry (DSC)

DSC was performed using a TA Instruments 2920 differential scanningcalorimeter. Temperature calibration was performed using NIST-traceableindium metal. The sample was placed into an aluminum DSC pan, coveredwith a lid, and the weight was accurately recorded. A weighed aluminumpan configured as the sample pan was placed on the reference side of thecell. Modulated DSC data (see, e.g., FIG. 23) were obtained on a TAInstruments Q2000 differential scanning calorimeter equipped with arefrigerated cooling system (RCS). Temperature calibration was performedusing NIST-traceable indium metal. The sample was placed into analuminum DSC pan, and the weight was accurately recorded. The pan wascovered with a lid perforated with a laser pinhole, and the lid washermetically sealed. A weighed, crimped aluminum pan was placed on thereference side of the cell. Data were obtained using a modulationamplitude of ±1° C. and a 60 second period with an underlying heatingrate of 2° C./minute from −50 to 220° C. The reported glass transitiontemperatures are obtained from the inflection point of the step changein the reversing heat flow versus temperature curve.

Proton Nuclear Magnetic Resonance (1H NMR)

The solution NMR spectra were acquired with a Varian UNITYINOVA-400spectrometer. The samples were prepared by dissolving a small amount ofsample in DMSO-d6 containing TMS.

Pawley Refinement

Indexing and subsequent Pawley refinement provides the most accuratedetermination of unit cell volume and cell parameters from XRPD data.These computations were performed using TOPAS 4.2, 2009, Bruker AXSGmbH, Karlsruhe, Germany. The background was modeled using a 3rd orderChebychev polynomial. Peak shape was modeled using Lorentziancrystallite size broadening and axial divergence was modeled using thefull axial model. Peak positions were allowed to vary by fitting theunit cell parameters. Whole pattern Pawley refinement was performed onall parameters simultaneously to a convergence of 0.001 in χ2.

Thermogravimetric Analysis (TGA)

TG analyses were performed using a TA Instruments 2950 thermogravimetricanalyzer. Temperature calibration was performed using nickel andAlumel™. Each sample was placed in an aluminum pan and inserted into theTG furnace. The furnace was heated under a nitrogen purge. The dataacquisition parameters are displayed above each thermogram in the Datasection of this report. The method code on the thermogram is anabbreviation for the start and end temperature as well as the heatingrate; e.g., 25-350-10 means “from 25 to 350° C., at 10° C./min.”

EXAMPLES Example 1 Salt Screen

Fourteen salts were targeted; however, only six glycopyrrolate saltswere successfully isolated and characterized: acetate, benzoate,edisylate, oxalate, hydrogen sulfate, and tosylate. These salts wereformed either by (1) reaction of glycopyrrolate bromide with silversalts of salt formers, or (2) reaction of glycopyrrolate acetate withsalt former acids.

Example 2 Glycopyrrolate Benzoate

The glycopyrrolate benzoate salt was prepared only once using route (1)from Example 1. Glycopyrrolate benzoate was generated on reactingsaturated aqueous solutions of each glycopyrrolate bromide with silverbenzoate at approximately 92° C., followed by filtration and subsequentlyophilization of the mother liquor. The material was thenrecrystallized in acetone/MTBE (1/2, vol/vol) and sonicated to formwhite crystalline solids. An XRPD pattern associated with this materialis in FIG. 12. Proton NMR showed the presence of equimolar amounts ofthe glycopyrrolate and benzoate species, as well as water. Thermalanalysis of the sample showed a single endotherm with a peak maximum of79° C. in the DSC thermogram concomitant with a 3.5 wt % loss between 25and 80° C. in the TG trace. The weight loss was equivalent toapproximately one mole of water indicating the formation of amonohydrate.

Example 3 Di-Glycopyrrolate Edisylate

Di-glycopyrrolate Edisylate salt was formed using process (2) fromExample 1. A second molar equivalent of glycopyrrolate acetate was addedto the reaction mixture of glycopyrrolate acetate and a minor amount ofsilver acetate and one molar equivalent of 1,2-ethanedisulfonic acid inethyl acetate/isopropanol (83/17, vol/vol). The mixture was stirred forapproximately five minutes before the resulting grey solids wereisolated and dried under vacuum at ambient temperature for one day. Thedried solids were crystalline with a minor amount of silver acetate byXRPD (FIG. 14). The XRPD pattern was successfully indexed whichindicated that the material was composed of a single crystalline phase.Proton NMR spectroscopy confirmed the presence of two moles ofglycopyrrolate per mole of edisylate, and water. Thermal analysis of thesample showed a 3.8 wt % loss between 25 and 95° C. in the TG trace andan endotherm with a peak maximum at 103° C. in the DSC thermogram. Themass loss equates to approximately two moles water indicating adihydrate.

Example 4 Glycopyrrolate Oxalate

Glycopyrrolate oxalate was prepared using process (2) from Example 1.Equimolar amounts of oxalic acid and glycopyrrolate acetate weredissolved in methanol then fast evaporated and dried under vacuum. Theresulting glassy, gel-like material was recrystallized by slurrying inethyl acetate to produce grey solids that were then dried under vacuumbefore analysis by XRPD and proton NMR spectroscopy. The XRPD patterncan be found in FIG. 16.

Example 5 Glycopyrrolate Hydrogen Sulfate

Glycopyrrolate hydrogen sulfate was prepared as a mixture with a traceamount of silver sulfate using process (2) from Example 1. Equimolaramounts of glycopyrrolate acetate and sulfuric acid were stirred inanhydrous ethyl acetate for approximately one day before the resultingmaterial was isolated and dried under vacuum. The solids werecharacterized by XRPD, proton NMR spectroscopy, thermal techniques andelemental analysis. The XRPD pattern was unique and contained a traceamount of silver sulfate (FIG. 17). The XRPD pattern was successfullyindexed except for the silver sulfate peak at 28.35° 2θ, indicating thatthe glycopyrrolate hydrogen sulfate salt was composed of a singlecrystalline phase. The silver sulfate was likely formed from the silveracetate present in the glycopyrrolate acetate starting material. The NMRspectrum was consistent with a 1:1 ratio of a glycopyrrolate andhydrogen sulfate. Thermal analysis showed a major sharp endotherm with apeak maximum at 160° C. and a second endotherm with a peak maximum at169° C., and a negligible weight loss of 0.2 wt % between 25 and 180° C.Elemental analysis confirmed the anhydrous salt stoichiometry.

Example 6 Glycopyrrolate Tosylate

In a dark room, silver tosylate (3.5 g) was dissolved in water (˜100 mL)by sonication. The solution was heated to approximately 40° C. andadditional water was added (˜15 mL). An equimolar amount ofglycopyrrolate bromide (5 g) (mixture of R,S and S,R diastereomers) wasadded and immediately resulted in a yellow precipitate. The slurry wasstirred at approximately 40° C. overnight, and then slowly cooled whilestirring to ambient temperature. At ambient temperature, the solids werevacuum filtered and the wet cake was washed three times withapproximately 10 mL of water. The mother liquor was collected andfiltered two times through a 0.2 μm nylon filter with glass microfiber(GMF). A clear solution was observed after filtration and waslyophilized at approximately −50° C. After 6 days, a mixture of white,needle-like and slightly sticky, glassy solids was observed. Toluene(˜20 mL) was added, and the slurry was briefly sonicated and thenstirred at ambient temperature. Additional toluene (˜80 mL) was addedfor easier stirring, and the mixture was allowed to stand at ambientconditions for 1 day. Solids of glycopyrrolate tosylate were collectedby vacuum filtration and vacuum drying at ambient temperature for 1 day.

Example 7 Preparation of Glycopyrrolate Tosylate

A slurry of equimolar amounts of glycopyrrolate acetate andp-toluenesulfonic acid was prepared in isopropanol (1 mL). The mixturewas stirred at ambient temperature. Additional isopropanol (0.5 mL) wasadded to improve stirring, and the mixture was stirred overnight. Solidsof glycopyrrolate tosylate were isolated by vacuum filtration andanalyzed.

Example 8 Preparation of Glycopyrrolate Tosylate Form D

Glycopyrrolate tosylate (1.0569 g) made from Example 6 was dissolved in4 mL ACN/H₂O (50/50 vol/vol) by sonication. The solution was filteredthrough 0.2 μm nylon filter into a clean vial. The solvent was allowedto partially evaporate from an open vial under ambient conditions.Further evaporation was subsequently performed under nitrogen gas flow.A gel resulted which was vacuum dried at 40° C. for 1 day. Toluene (5mL) was added and the mixture was sonicated for approximately 10 minutescausing white solids to precipitate. The mixture was stirred at ambienttemperature for 1 day. The solids were isolated by vacuum filtration andthe wet cake was washed with approximately 10 mL of toluene. The solidswere vacuum dried at ambient temperature for 1 day. After vacuum dryingthe solids were placed in a vial which remained uncapped and placedinside a relative humidity chamber (˜97%). The chamber was placed insidean oven at 41° C. After 6 days, the solids were analyzed by XRPD showingForm D.

Example 9 Single Crystal Preparation of Form D

Glycopyrrolate tosylate (54.9 mg) made from Example 6 was dissolved inEtOAc/DMF (87/13 vol/vol) at approximately 55° C. at 24 mg/ml. Thesolution was hot filtered through a 0.2 μm nylon filter into apre-warmed vial. The vial containing the solution was first placed in adry ice/acetone bath and then in a freezer (approximately −25 to −10°C.). After 3 days, the solution was re-heated to approximately 50° C.and additional EtOAc was added for 96/4 EtOAc/DMF (vol/vol) at 7 mg/ml.The solution was quickly removed from elevated temperature and placed inthe freezer. Solids were isolated by decanting the solvent and dryingthe solids under ambient conditions.

Single Crystal Data Collection

A colorless chunk of C₂₆H₃₇NO₇S [C₇H₇O₃S, C₁₉H₂₈NO₃, H₂O] havingapproximate dimensions of 0.23×0.20×0.18 mm, was mounted on a fiber inrandom orientation. Preliminary examination and data collection wereperformed with Cu Kα radiation (λ=1.54184 Å) on a Rigaku Rapid IIdiffractometer equipped with confocal optics. Refinements were performedusing SHELX97.

Example 10 Preparation of Dehydrated Form D

A mixture of glycopyrrolate tosylate solids, including Form C and FormD, and a trace amount of silver tosylate was kept over P₂O₅ at ambienttemperature for 18 days. The resulting solids were composed of a mixtureof dehydrated Form D with a trace of silver tosylate as shown by XRPDanalysis.

Example 11 Preparation of Form C Glycopyrrolate Tosylate

Glycopyrrolate tosylate Form D, containing trace amounts of Form C andsilver tosylate, was heated on an Anton Paar TTK 450 stage and XRPDpatterns were collected in situ in the range 3.5-26° (2θ). All heatingsteps were at approximately 10° C./min. The stage was heated inincremental steps of 20° C. from 25 to 125° C. At each step, an XRPDpattern was collected over approximately 4 minutes. The stage was thenheated to 135° C. and an XRPD pattern was collected over approximately16 minutes and after heating further to 145° C., a pattern was collectedin approximately 31 minutes. The sample was subsequently cooled to 25°C. at approximately 24° C./min, upon which a final XRPD pattern wascollected over approximately 16 min. The XRPD pattern of this finalpattern was indexed as Form C.

Example 12 Preparation of Form C Glycopyrrolate Tosylate

Glycopyrrolate tosylate Form D from Example 6 was heated to anapproximate temperature in the range 143-149° C. under a continuousnitrogen purge for approximately 3.3 hours. The vial containing thesolids was capped, placed on a lab bench and allowed to cool down toroom temperature. At room temperature, the vial was placed in a jarcontaining P₂O₅. The sample was prepared for XRPD analysis undernitrogen which confirmed production of Form C.

Example 13 Preparation of Form C Glycopyrrolate Tosylate

Glycopyrrolate tosylate (59.5 mg) from Example 6 was dissolved inacetone at approximately 50° C. at 27 mg/ml. The solution was hotfiltered through a 0.2 μm nylon filter into a pre-warmed vial. The vialwas capped and left on the hot plate which was subsequently turned offto allow the sample to cool slowly to ambient temperature. At ambienttemperature the solution was stirred causing white solids toprecipitate. The solids were isolated by vacuum filtration and the wetcake was washed with approximately 2 ml of acetone. XRPD analysisresulted in Form C.

Example 14 Amorphous Glycopyrrolate Tosylate

Glycopyrrolate tosylate from Example 6 was melted and cooled repeatedlyuntil the majority of the solids had the appearance of a glass bymicroscopy. XRPD analysis indicated that the “glassy” sample wasobserved to be amorphous. A 2.2% weight loss was observed by TGA from 25to 250° C. of the amorphous glycopyrrolate tosylate. The onset of theglass transition temperature was measured at 11.6° C.

Example 15 Preparing Crude Threo Glycopyrrolate Tosylate

Cyclopentylmandelic acid is combined with 1,1′-carbonyldiimidazol intoluene and is heated and stirred. N-methyl-3-pyrriolidinol is addedwhile stirring and heated in toluene. The reaction mixture is thencooled and washed with purified water. The isolate toluene layer is thenreduced to a concentrate of the glycopyrrolate base.

5-Nitroisophthalic acid (1 eq.) is dissolved in methanol (20 vol) atroom temperature with moderate agitation. The glycopyrrolate base (1eq.) obtained above is then added. Once crystallization is initiated,the mixture is stirred at room temperature. The solids are thenrecovered in a filtration centrifuge and washed with methanol. The crudeproduct is then suspended in methanol and stirred at approximately 65°C. for one hour, then cooled to 20° C. and stirred for a further 4hours. The product is again recovered, washed with methanol, partiallydried and discharged as wet glycopyrrolate 5-nitroisophthalate. Theratio of threo:erythro diastereomeric pairs is typically 96:4. Thethreo-glycopyrrolate base is obtained by treatment of the wet5-nitroisophthalate salt with aqueous sodium hydroxide and toluene.

The threo-glycopyrrolate base is dissolved in acetone and treated with aslight excess of methyl-p-toluenesulfonate. The completion of reactionis monitored by TLC until the remaining base is NMT 2%. The crudeglycopyrronium tosylate is recovered and washed twice with acetone. Thewet cake obtained is dried under vacuum at elevated temperature.

Example 16 Pure Threo Glycopyrrolate Tosylate

The product of Example 15 is triturated in purified water and recoveredand washed with cold purified water. The wet cake is then dissolved inwater with agitation. The solution obtained is cooled and held untilcrystallization begins. The mixture is then further cooled and agitatedand the product is recovered and washed with cold purified water. Theproduct then undergoes a second recrystallization under similarconditions. The product is tray dried at not more than 40° C. withoutvacuum for a minimum time until the water content is between about2.5%-4.0%.

Example 17a Preparing an Aqueous Solution of Glycopyrrolate Tosylate

To a vessel of appropriate size, add purified water, citric acid andsodium citrate dihydrate and dissolve by mixing. Add dehydrated alcohol;initiate mixing and continue to mix until a homogenous clear solution isobtained. Continue mixing and add solid glycopyrrolate tosylate and mixuntil the glycopyrrolate tosylate is dissolved and the solution ishomogenous. The solution should be clear and colorless or pale yellowwith a pH of between about 4.0 and about 5.0 at about 25° C.

Example 17b Preparing an Aqueous Solution of Threo GlycopyrrolateTosylate Using Form D

To a vessel of appropriate size, add purified water, citric acid andsodium citrate dihydrate and dissolve by mixing. Add dehydrated alcohol;initiate mixing and continue to mix until a homogenous clear solution isobtained. Continue mixing and add Form D glycopyrrolate tosylate and mixuntil the glycopyrrolate tosylate is dissolved and the solution ishomogenous. The solution should be clear and colorless or pale yellowwith a pH of between about 4.0 and about 5.0 at about 25° C.

Example 18 Filling a Pouch and Pad

Each pouch is formed, heat sealed on three sides; bottom, and outeredges. A pad is folded and cut to size, and with a final fold in half,one pad is inserted into each preformed pouch through the open top.About 2.8 g of the glycopyrrolate tosylate product of Example 15 isadded through the open top of each pouch wetting the enclosed pad. Thetop side of the pouch is heat sealed.

General Preparation of Solid Dispersions

Solutions of excipient and glycopyrrolate tosylate Form D were dissolvedin water, ethanol/water or dioxane/water, filtered through a 0.2-μmnylon fiber membrane, dropwise, into a vial submerged in a liquidnitrogen bath. The addition rate of the solution was monitored so thateach drop of the sample was frozen prior to the next drop being added.The samples were placed on dry ice and immediately transported to aLABCONCO Triad Series lyophilizer and dried. After drying, the solidswere isolated and stored over desiccant in a freezer. All samples wereremoved from the freezer and warmed to ambient temperature in adesiccator prior to analysis. Attempts were made to limit the amount oftime the sample experienced at ambient humidity prior to analysis.Excipients were purchased from commercial suppliers and used as receivedincluding: PVP K-29/32 ISP Technologies, Inc. Wayne N.J; Kollicoat IR,Kollidon VA 64: BASF SE, Ludwigshafen, Germany; HPMCAS: Shin-EtsuChemical Company Ltd., Tokyo, Japan; PVP K-90: Sigma-Aldrich, Inc., St.Louis Mo., USA. This general procedure was followed in the examples setforth Table 8 below using the weights of excipient, glycopyrrolatetosylate and solvent choice as indicated.

TABLE 8 Solid Dispersion Examples Wt. Example Excipient GlycopyrrolateWt. Excipient Number (Loading) Tosylate (mg) (mg) Solvent 19 HPMCAS 79.179.6 H₂O/Dioxane (1:1) [1:3] 20 Sucrose 10.3 89.7 H₂O (9:1) 21Kollicoat ® 82.0 80.1 H₂O IR (1:1) 22 Kollicoat ® 10.5 90.2 H₂O IR (9:1)23 Soluplus ® 78.2 79.5 H₂O/Dioxane (1:1) [1:1] 24 PVP 80.4 80.5 H₂OK-29/32 (1:1) 25 PVP 11.3 89.5 H₂O K-29/32 (8:1) 26 PVP K-90 79.5 80.4H₂O/EtOH (1:1) [5:1] 27 Kollidon ® 78.5 79.8 H₂O VA 64 (1:1)

All examples presented are representative and non-limiting. Theabove-described embodiments may be modified or varied, without departingfrom the invention, as appreciated by those skilled in the art in lightof the above teachings. It is therefore to be understood that, withinthe scope of the claims and their equivalents, the invention may bepracticed otherwise than as specifically described.

What is claimed is:
 1. A method of treating hyperhidrosis comprisingtopically administering a therapeutically effective amount of apharmaceutically acceptable solution of glycopyrrolate tosylatecomprising a racemic mixture of(R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate and(S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate or solvate thereof to the skin of a mammal,wherein the pH of said pharmaceutically acceptable solution is between3.5 and 5.5 at 25° C.
 2. The method of claim 1, wherein said mammal is ahuman.
 3. The method of claim 1, wherein said pharmaceuticallyacceptable solution is applied to the axilla.
 4. The method of claim 1,wherein said pharmaceutically acceptable solution is applied to thehands.
 5. The method of claim 1, wherein said pharmaceuticallyacceptable solution is applied to the feet.
 6. The method of claim 1,wherein said pharmaceutically acceptable solution is applied to thegroin, face, back or abdomen.
 7. The method of claim 1, wherein saidadministering is with an absorbent pad.
 8. The method of claim 1,wherein said administering is with an absorbent pad, said pH of saidpharmaceutically acceptable solution is between 4.0 and 5.0 at 25° C.,and said pharmaceutically acceptable solution further comprises a buffercomprising citric acid, sodium citrate, or a combination thereof.
 9. Themethod of claim 8, wherein said pharmaceutically acceptable solutionfurther comprises ethanol.
 10. The method of claim 1, wherein saidpharmaceutically acceptable solution is an aqueous solution.
 11. Themethod of claim 1, wherein said pharmaceutically acceptable solution isa hydroalcoholic solution.
 12. The method of claim 7, wherein saidabsorbent pad comprises polypropylene.
 13. The method of claim 12,wherein said absorbent pad is substantially polypropylene.
 14. Themethod of claim 13, wherein said absorbent pad is 100% polypropylene.15. The method of claim 10, wherein said hydroalcoholic solutioncomprises one or more buffers and ethanol.
 16. The method of claim 1,wherein said pharmaceutically acceptable solution further comprises oneor more of a binding agent or a film-forming agent.
 17. The method ofclaim 16, wherein said binding agent is povidone and said film-formingagent is a butyl ester of a polyvinylmethylether/maleic anhydride acidcopolymer.
 18. The method of claim 1, wherein said therapeuticallyeffective amount of a pharmaceutically acceptable solution ofglycopyrrolate tosylate is about 2.8 g.
 19. The method of claim 7,wherein said absorbent pad contains said pharmaceutically acceptablesolution of glycopyrrolate tosylate comprising about 0.15% by weightanhydrous citric acid, about 0.06% sodium citrate dihydrate by weight,between about 57 to about 59.5% by weight of dehydrated ethanol, andbetween about 1% and about 6% by weight of said glycopyrrolate tosylate.20. The method of claim 1, wherein said hyperhidrosis is primaryaxillary hyperhidrosis.
 21. The method of claim 1, wherein saidhyperhidrosis is palmar or plantar hyperhidrosis.